Abstract
BackgroundAdministration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects.MethodsThe present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models.ResultsSystemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP.ConclusionsOur findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway.Trial registrationThis study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.
Highlights
Lipopolysaccharide (LPS) is a component from the cell wall of Gram-negative bacteria that binds to toll-like receptor 4 and triggers secretion of pro-inflammatory cytokines in a dose-dependent manner [1, 2]
Systemic injection of LPS was associated with significantly lower concentrations of tryptophan and kynurenine at the 240 min (4 h) timepoint compared to placebo (Fig. 2, top left and top right panel)
Forty-eight hours after administration, kynurenine and quinolinic acid (QUIN) were higher in the LPS treated condition compared to the placebo-treated condition (Fig. 2, top right and bottom left panel)
Summary
Lipopolysaccharide (LPS) is a component from the cell wall of Gram-negative bacteria that binds to toll-like receptor 4 and triggers secretion of pro-inflammatory cytokines in a dose-dependent manner [1, 2]. LPS-induced inflammation, or artificial endotoxemia, is an established model for experimental, systemic inflammation in humans. It reliably causes a febrile, systemic inflammatory response in healthy individuals and is the most widely accepted model to study the pathophysiology of human host response to infection [3]. It is well known that the activation of the immune system initiates the kynurenine pathway (Fig. 1) and thereby induces tryptophan degradation [16]. Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects
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